remdesivir (trade name: veklury) most likely …...(b) start late (at d11 or d12)(b) median days to...
TRANSCRIPT
Remdesivir (trade name: Veklury)Most likely ineffective for COVID-19
MedCheck Editorial teamJuly 17 2020
d5 after inoculationonset of symptom
d3 after inoculationRNA is appeared
in plasma
controld0~3mg
d210mg,d3~3mg
d3~10mgd310mg,d4~3mgd0 :Ebola virus was inoculated i.m.
d2~3mg
2
If enough remdesivir is administered before the onset of symptoms it reduced mortality. No test in which it was administered after the onset of symptoms was done.
4) Warren TK et al. Nature 2016;531:381-5.
Animal experiment(1):
d3 after inoculationRNA is appeared
in plasma
Remdesivir 24 hr after inoculation
Symptom onset in control group was d3
All died within 8 days without remdesivir
3
Animal experiment(2):5) Lo MK et al. Sci Transl Med2019;11:eaau9242.
If remdesivir is administered one day after the inoculation and before the onset of symptoms, it reduced mortality. However no animal test was done in which remdesivir is administered after the onset of clinical symptoms.
Remdesivir start one day before and
12 hrs after inoculation
Remdesivir start 12 hrs after inoculation
D1: Symptom onset
control
Remdesivir start one day before inoculation
inoculation
4
Control one day before 12 hrs after
Animal experiment(3):6) de Wit E et al. Proc Natl Acad Sci 2020;117:6771-6.
Prophylactic: remdesivir was started at one day before inoculationTherapeutic: remdesivir was started at 12 hrs after inoculation
WBP: whole-body plethysmography (pulmonary function test)
Symptom onset is at d2
Mice were treated with 25mg/kg remdesivir b.i.d 50mg/kg/d⇒HED=4mg/kg/d (240mg/d for 60kg BW)
5
7) Sheahan TP et al. Transl Med. 2017:9(396):eaal3653.
control
Animal experiment(4):
Prophylactic: remdesivir was started at one day before inoculationTherapeutic: remdesivir was started at one day after inoculation
No experiments was done in which remdesivir was commenced after onset of disease.
control
Start 12hrs after Radiograph scores
6
Therapeutic: This is rather prophylactic because administration started before onset of symptoms
Symptom onset
These effects are not remarkable.
Animal experiment(5):8) Williamson BN et al. bioRxiv 2020.04.15.043166. [Preprint.]
Control
Remdesivir
Remdesivir is the least effective among 4 agents including 3 monoclonal antibodies for reduction of mortality
7
Mortality 50% 53% 35% 34%
9) Mulangu S et al. NEJM 2019: 381 (24): 2293-2303.
Remdesivir is not a remedy for Ebola virus infection (1)
53.1
49.7
35.1
33.5
0 10 20 30 40 50 60
レムデシビル
モノクローナル抗体3
モノクローナル抗体2
モノクローナル抗体1
Mortality (%)
Less effective for reduction of mortality than any othermonoclonal antibodies (more than doubled mortality)
Compared with 2 kinds of monoclonal antibody, remdesivir increasesmortality by more than 2-fold from Ebola virus infection: This indicates
that Remdesivir is not a remedy for Ebola virus infection. 8
Remdesivir is not a remedy for Ebola virus infection (2)
Monoclonal antibody 1
Monoclonal antibody 2
Monoclonal antibody 3
RemdesivirOdds ratio of mortality: 2.25 (95%CI: 1.44, 3.51, p=0.0003) vs monoclonal antibody 1
2.10(95%CI: 1.37, 3.23, p=0.0007) vs monoclonal antibody 2
Time course of special approval of Remdesivirdate Source/facilities contents
April 23 STAT(a news site in US)
Published screen shot of the summary of theLancet [10] disclosed by WHO.
April 29 Wuhan RCT Online publication at Lancet [10]:A placebo controlled RCT
April 29 NIH (US) Press release Main results of ACTT [2] by National Institute ofAllergy and Infectious Diseases (NIAID) :NCT04280705)
April 29 Gilead Sciences Press release of SIMPLE trialMay 1 FDA (US) EUA: Emergency Use Authorization
May 4 Gilead Sciences Submitted approval application to MHLW
May 7 Japanese Advisory Panelfor pharmaceuticals
Held by web-conference
May 7 Japanese MHLW Special approval of remdesivir first in the woldMay 22
May 27
ACTT by NIAID Online publication at NEJM [11]A placebo controlled RCT
SIMPLE trial Online publication at NEJM [12]Comparison of 5 day- and 10 day-treatment
9
WuhanRCT(1)
10
10) Wang Y et al .Lancet. 2020: 395(10236):
1569-1578.
Wuhan RCT(2): Main baseline characteristics No difference
11
P=0.037<>
Others are not different12
Wuhan RCT(3) Different baseline characteristics
14
10
11
15
14
13
0 5 10 15
レムデシビル
プラセボ
レムデシビル
プラセボ
レムデシビル
プラセボ
11日以後
に開始
10日以前
に開始
全体
Mortality at day 28 (%)
P=0.82
P=0.56
P=0.51
Mortality at d28d9, d10
d11, d12
13
Wuhan RCT(4) Day 28 mortality by early or late commencement of remdesivir
Placebo Remdesivir
Placebo Remdesivir
Placebo Remdesivir
Overall
Start at d9 or d10
Start at d11, or d12
(A) Start early (at d9 or d10) median days to clinical improvement 18 days vs 23 days
Hazard ratio: 1.52; 95%CI:0.95 - 2.43
(B) Start late (at d11 or d12)(B)median days to clinical improvement
23 days vs 24 days
Hazard ratio: 1.07; 95% CI, 0.63 - 1.83
Wuhan RCT (5):Kaplan-Meier curve of clinical improvement(ITT)
14
Figure 2: Time to clinical improvement in the intention-to-treat Population: Adjusted hazard ratio for randomisation stratification was 1・25 (95% CI: 0・88–1・78). *Including deaths before day 28 as right censored at day 28, the number of patients without clinical improvement was still included in the number at risk.
Serious AdverseEvents
Adverse Events(AEs)
Most serious adverse events were not different
15
Wuhan RCT(6):
Events leading to
discontinuation
Respiratory failure/ARDS: p=0.20
Non-significant increase of respiratory failure/ARDS leading to discontinuation
was observed in Remdesivir group. Respiratory failure and ARDS are main
symptoms of COVID-19. What does this mean? 16
Wuhan RCT(7): Serious AdverseEvents
Upper respiratory tractViral load
Wuhan RCT(8):Accumulated rate of undetectable viral RNA in upper respiratory tract specimen in viral positive population
Undetectable viral RNA in Remdesivir group was nearly 10 % lower than control groupespecially in the survivours.
What does this mean? 17
lower respiratory tract
BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infectioncontrol purposes only.RESULTS: A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).CONCLUSIONS: Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705.) Adjusted HR for death= 0.74(95%CI: 0.50 to 1.10)
18
ACTT trial (1)11) Beigel JH et al. NEJM. 2020 May 22.
19
ACTT trial(2) Baseline characteristics
23% vs 28%P=0.059
Level 7: Receiving invasive
mechanical ventilationor ECMO
ACTT trial(3) Fig. 2 Kaplan-Meier estimates of cumulativerecoveries by baseline severity.
20
OverallLevel 4.Not receiving oxygen
5.Receiving oxygen
Significant difference only in this subgroup
6.High flow oxygen ornoninvasive ventilator
7.Invasive ventilatoror ECMO
No difference
No difference
No difference
21
5. O24. No O2 6.High O27.Invasive
MV/ECMO
2.9% vs 11%
ACTT trial(4)
22Unnatural: mortality of placebo group is not different between subgroup 5 and more severe subgroup 6/7
ACTT trial(5) Kaplan-Meier Estimate of Survival by baseline
It is very unnatural that there are almost no difference of mortality in placebo groups,
because the baseline severity is greatly different.
OverallLevel 4.Not receiving oxgen
5.Receiving oxygen 6.High flow oxygen ornoninvasive ventilator
7.Invasive ventilatoror ECMO
ACTT trial (6) :Comparison of day 14 mortality by baseline severity(Kaplan-Meier estimate )
In all subgroups by baseline severity except level 5, mortality risk was not different between Remdesivir arm■ and placebo group□. Only in the subgroup of level 5 (receiving O2) mortality was extremely different. But in the subgroup of level 5, mortality of placebo group is unnaturally high (almost the same as those of the subgroups 6 or 7 with greater baseline severity) and mortality of remdesivir group is unnaturally low (almost the same as that of the subgroup 4). It is very hard to find appropriate reasons why Remdesivir was effective only in the level 5. 23
1.5 2.4
15.2
11.3
2.5
10.9
14.7 14.1
2.0
6.7
15.0
12.7
02468
10121416
4. No O2 5 O2 6. High O2 7. InvasiveMV/ECMO
Mor
talit
y (%
)
Rmdesivir Placebo Total
4.Without O2 5.Receiving O2 6.High flow O2 7.Invasive MV/ECMO
Remdesivir
ACTT trial (7) Summary: Critical appraisal of preliminary report 1. There was no significant difference between remdesivir arm and placebo arm except one, proportion of the level 7 of the baseline severity which was non-significantly different (p=0.059).
2. Comparing the improvement of clinical symptoms and the overall survival by baseline severity, there was no difference between both groups in the sub groups of levels 4, 6 and 7. Difference was only observed in the subgroup of level 5 (receiving oxygen).
3. At the level 5, all-cause mortality of the placebo group was unnaturally high, and there was no significant difference from that at the levels 6 and 7.
4. On the other hand, all-cause mortality of the Remdesivir group in the level 5 was unnaturally low, and there was almost no difference from that at the level 4.
5. If Remdesivir group and placebo group of the subgroup level 5 were combined, all-cause mortality of the level 5 was at the mid point between levels 4 and 6 or 7 and this is very natural biologically.
6. Taken together, it is doubtful whether 421 patients in the subgroup of level 5 was appropriately allocated at randomization.
7. Unless details of baseline characteristics of the Level 5 subgroup (222 patients in the remdesivir group and 199 patients in the placebo group) are available and it is confirmed that there is no difference in the baseline characteristics, the results of this study remains unreliable. The baseline characteristics include distribution of oxygen partial pressure or oxygen saturation, distribution of laboratory data related to severity, such as creatinine level and severity score such as APACHE II, MEDS, SAPS II or SOFA. APACHE II = Acute Physiology and Chronic Health Evaluation II, MEDS = Mortality in Emergency Department Sepsis Score, SAPS II = New Simplified Acute Physiology Score, SOFA = Sequential Organ Failure Assessment.
24
25
13)Goldman JD et al NEJM 2020 May 27
SIMPLE trial (1)
26
SIMPLE trial(2)
P=0.021 According to the Japanese labelBetter outcome in 5-day group
1.death + 2. invasive MV/ECMO5-day vs 10-day
16.0% vs 27.4%OR=0.50 (95%CI:0.31-0.82)
p=0.006
10-day vs 5-dayOR= 1.98 (1.28, 3.23)
27
SIMPLE trial (3) Results
5-day group improved better than 10-day group.
Moreover, 5 day group died or become deteriorated less than 10-day group.
5-day group is significantly superior to 10-day group
28
SIMPLE trial (4) Results (2):Main results
10-day vs 5-dayOR (95%CI), Pvalue
0.64(0.43,0.96), p=0.030
0.95(0.58,1.57), p=0.86
1.98(1.21,3.23), p=0.006
1.98 (1.27, 3.11), p=0.003
2.42 (1.33, 4.40), p=0.003 9.0
21.0
16.0
19.5
64.5
19.3
34.5
27.4
18.8
53.8
0 10 20 30 40 50 60 70
CardiorespiratorySAEs
Any serious AEs
1.Death + 2.Invasive MV
Others (3,4,5)
7.Discharge alive+6.No O2
Proportion (%)
10-day
5-day
O2+ 6. Without O2
SAEs were 2-fold more reported in 10-day group than 5-day group. Especially cardiorespiratory SAE (ARDS, (acute) respiratory failure, and septic shock) were 2.4-fold more frequently reported (p=0.003).
SIMPLE trial (5)Adverse events
(AEs) And Serious AEs (SAEs)
Any SAEs double10-day vs 5-day
OR=2.0 (1.3, 3.1), p=0.003
Cardiorespiratory SAEs10-day vs 5-day
OR=2.4 (1.3-4.4),p=0.003
29